Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons.
Critical role of large-conductance calcium- and voltage-activated potassium channels in leptin-induced neuroprotection of N-methyl-d-aspartate-exposed cortical neurons.
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DOI：
10.1016/j.phrs.2014.06.010
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发表时间：
2014-09
影响因子：
9.3
通讯作者：
Taglialatela, Maurizio
中科院分区：
文献类型：
--
作者：
Mancini, Maria;Soldovieri, Maria Virginia;Gessner, Guido;Wissuwa, Bianka;Barrese, Vincenzo;Boscia, Francesca;Secondo, Agnese;Miceli, Francesco;Franco, Cristina;Ambrosino, Paolo;Canzoniero, Lorella Maria Teresa;Bauer, Michael;Hoshi, Toshinori;Heinemann, Stefan H.;Taglialatela, Maurizio
关键词：
在本研究中，脂肪因子瘦素的神经保护作用，并参与的分子机制，已在大鼠和小鼠皮层神经元暴露于N-甲基-D-天冬氨酸（NMDA）在体外进行了研究。在大鼠皮层神经元，瘦素引起神经保护作用对NMDA诱导的细胞死亡，这是浓度依赖性的（10-100 ng/ml）和最大的脂肪因子预孵育2小时前的神经毒性刺激。在大鼠和小鼠皮层神经元中，瘦素诱导的神经保护作用被Paxilline完全拮抗（Pax，0.01-1 μM）和伊比利亚毒素（Ibtx，1-100 nM），两种Ca 2+和电压激活K+通道阻滞剂（Slo 1 BK通道），具有EC 50（Pax和Ibtx分别为38±10 nM和5±2 nM），接近于Pax和Ibtx诱导的BK通道阻断报告的值; BK通道开放剂NS 1619（1-30 μM）对NMDA诱导的兴奋性毒性具有浓度依赖性保护作用。此外，缺乏一个或两个等位基因编码Slo 1 BK通道孔形成亚基的小鼠皮层神经元对瘦素诱导的神经保护不敏感。最后，瘦素暴露剂量依赖性（10-100 ng/ml）增加大鼠皮层神经元细胞内Ca 2+水平。总之，我们的研究结果表明，Slo 1 BK通道激活细胞内Ca 2+水平的增加是一个关键步骤，瘦素诱导的神经保护在体外NMDA暴露的皮层神经元，从而突出瘦素为基础的干预通过BK通道激活作为一个潜在的战略，以对抗神经退行性疾病。
In the present study, the neuroprotective effects of the adipokine leptin, and the molecular mechanism involved, have been studied in rat and mice cortical neurons exposed to N-methyl-D-Aspartate (NMDA) in vitro. In rat cortical neurons, leptin elicited neuroprotective effects against NMDA-induced cell death which were concentration-dependent (10–100 ng/ml) and largest when the adipokine was preincubated for 2 hours before the neurotoxic stimulus. In both rat and mouse cortical neurons, leptin-induced neuroprotection was fully antagonized by Paxilline (Pax, 0.01–1 μM) and Iberiotoxin (Ibtx, 1–100 nM), two blockers of Ca2+- and voltage-activated K+ channels (Slo1 BK channels), with EC50s (38±10 nM and 5±2 nM for Pax and Ibtx, respectively) close to those reported for Pax- and Ibtx-induced BK channel blockade; the BK channel opener NS1619 (1–30 μM) induced a concentration-dependent protection against NMDA-induced excitotoxicity. Moreover, cortical neurons from mice lacking one or both alleles coding for Slo1 BK channel pore-forming subunits were insensitive to leptin-induced neuroprotection. Finally, leptin exposure dose-dependently (10–100 ng/ml) increased intracellular Ca2+ levels in rat cortical neurons. In conclusion, our results suggest that Slo1 BK channel activation following increases in intracellular Ca2+ levels is a critical step for leptin-induced neuroprotection in NMDA-exposed cortical neurons in vitro, thus highlighting leptin-based intervention via BK channel activation as a potential strategy to counteract neurodegenerative diseases.
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